tbuckley/cabot-search huggingface dataset:
P1643: EFFICACY OF RECOMBINANT HUMANTHROMBOPOIETIN ON CHILDREN IMMUNE THROMBOCYTOPENIA AND ITS INFLUENCING FACTORS
Authors: J. Ma, Z. CHEN, H. GU, R. WU
Journal: HemaSphere (2022)

Background: RhTPO can promote the production of platelets and its clinical value has been proved in adult ITP. However, there are little data on efficacy and safety in children ITP and still lacks predictive marker for efficacy. Considering THPO and MPL encode endogenous TPO and c-MPL, which participate in the biological efficacy of rhTPO, we speculate that the SNPs in THPO and MPL genes may have an impact on the efficacy of rhTPO. Aims: To verify the efficacy of rhTPO in children ITP and to explore the effects of THPO SNPs (rs6141 and rs956732) and MPL SNP (rs176067 and rs190983971) on the efficacy of rhTPO, in order to find predictive factors for rhTPO. Methods: We collect data from children ITP who received rhTPO and grouped them into severe newly-diagnosed ITP and ITP without response to first-line therapy. We evaluated the efficacy of rhTPO based on their platelet count and the severity of bleeding. NGS was used to test four targeted SNPs. The differences in SNPs distribution between different efficacy groups were compared. Results: Fifty-eight ITP were collected, 22 were severe newly diagnosed ITP and 36 were those with poor response to first-line therapy. The ORR and CR were respectively 79% and 58%. All had their bleeding grade significantly decreased after treatment, including those non-responders. The genotype distribution of THPO rs6141 is statistically different between the 2 groups, the CC genotype had a significantly increased tendency to develop into non-responders (CC/TT: OR=30.000, 95%CI=2.871-313.470). Besides, AA genotype of THPO rs956732 is also significantly increased in non-responders (AA/AG: OR=7.467, 95%CI=1.400-39.836). Image:Summary/Conclusion: rhTPO can effectively increase the platelet count and reduce bleeding severity of children ITP. The CC genotype at the rs6141 and AA genotype at the rs956732 of THPO are risk factors for the ineffectiveness of rhTPO.
P1375: SECOND PRIMARY MALIGNANCY AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: T.-D. Tan, L.-W. Chiou
Journal: HemaSphere (2022)

Background: Hematopoietic stem cell transplantation is a curative treatment for a variety of hematologic malignancies and some benign hematologic diseases. Besides chronic GVHD, second primary malignancy is also one of long-term adverse effect. Aims: We analyze the incidence and type of second malignancy in a single institute in 20 years. Methods: We retrospectively searched our post-transplant patients long-term follow up data between 2001 and 2021 and analyzed the incidence and pattern of second primary malignancy in our cohort. Results: Between 2001 and 2021, in our 380 patients cohort (184 auto- and 196 allo-transplant) with long-term survival 126 (68%) in autologous and 100 (51%) in allogeneic transplant, we had 12 patients of second primary malignancy including 5 of head and neck squamous cell carcinoma, 3 of MDS/AML, 1 of ALL, 1 of esophageal squamous cell carcinoma, 1 of breast cancer, and 1 of papillary thyroid cancer. Eight of them underwent allogeneic hematopoietic stem cell transplant had head and neck SCC, esophageal cancer, breast cancer, and papillary thyroid cancer. Four of whom underwent autologous transplant are MDS/AML and ALL. All 5 patients with head and neck cancer and one esophageal cancer patients had extensive chronic GVHD. Ten of our patients survived with 8 free of disease and one low risk MDS and one AML undergoing treatment. One hypo-pharyngeal and one esophageal cancer passed away after definitive cancer treatment. The accumulative incidence of second malignancy was 6% in 10 years and 16% in 19 years and post-autologous and post-allogeneic transplant were 5% vs 7% and 15% vs 17% in 10 years and 19 years, repectively. Image:Summary/Conclusion: Second primary malignancy in 20-year follow-up in our post-transplant cohort was 6% and 16% in 10 years and 19 years, respectively, and extensive chronic GVHD is associated with head and neck and esophageal squamous cell carcinoma.
P1297: ABERRANT MYCN EXPRESSION DRIVES ONCOGENIC HIJACKING OF EZH2 AS A TRANSCRIPTIONAL ACTIVATOR IN PERIPHERAL T CELL LYMPHOMA
Authors: M. Vanden Bempt, K. Debackere, S. Demeyer, Q. Van Thillo, N. Meeuws, J. Cools, D. Dierickx
Journal: HemaSphere (2022)

Background: Peripheral T cell lymphoma (PTCL) is a group of rare but aggressive hematological cancers arising from the malignant transformation of mature post-thymic T cells. PTCL patients currently face an unfavorable prognosis: approximately 75% of all PTCL patients relapse after first-line chemotherapy treatment. Consequently, 5-year survival rates are as low as 10-30%, which underscores the urgent medical need for new therapeutic options. Aims: The aim of this study was to characterize the oncogenic role of MYCN in PTCL development, and to identify novel targets for therapy. Methods: We performed RNA-sequencing on a cohort of 28 PTCL cases. In addition, we have generated a bone marrow transplant model of MYCN-driven T cell lymphoma, and we performed a thorough characterization of this model using RNA-sequencing and ChIP-sequencing. Downstream targets were validated using luciferase experiments, immunoprecipitation followed by mass spectrometry, flow cytometry and ex vivo treatments. Results: We observed aberrant overexpression of MYCN in 5/28 PTCL cases. In addition, we found that approximately 50% of the PTCL tumors is characterized by high expression of MYC target genes. Inducible expression of MYCN in lymphoid cells in a mouse model caused T cell lymphoma that recapitulated human PTCL with a MYC expression signature. Integration of mouse and human expression data identified EZH2 as a key downstream target of MYCN. Remarkably, EZH2 was found to be an essential co-factor for the transcriptional activation of the MYCN-driven gene expression program, which was independent of methyltransferase activity, but dependent on phosphorylation by CDK1. MYCN-driven T cell lymphoma was sensitive to EZH2 degradation or CDK1 inhibition, which displayed synergy with FDA-approved HDAC inhibitors. Summary/Conclusion: In conclusion, we identified MYCN as a recurrent aberrantly overexpressed gene in PTCL, and characterized the oncogenic mechanisms underlying MYCN overexpression, which led to the identification of novel targeted treatments for PTCL.
P1677: THROMBOSIS IN PREGNANT CANCER PATIENTS: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: S. Bos, H. Rier, H. Duvekot, I. Boere, M. Kruip
Journal: HemaSphere (2022)

Background: Cancer during pregnancy is a rare event, yet managing pregnant women with an active malignancy is challenging in many ways. One of these challenges is how to deal with the risk of venous thrombo-embolic events (VTEs). The risk of VTEs is increased in pregnancy, as well as during active malignancy. Because cancer during pregnancy is rare, little is known about the prevalence and risk of VTEs in these women. Aims: The objective of this study was to identify the prevalence of VTEs in pregnant patients with an active malignancy, and to see if there is a risk difference in various cancer types. Methods: A systematic search was performed in the databases of Embase, Medline, Web of Science, Cochrane, and Google Scholar from inception until the 5th of march 2021. The outcome was reviewed for title and abstract independently by the two first authors. Discrepancies were discussed to be included or excluded. From the included studies we reported the VTE incidence among pregnant cancer patients during and if available to 6 months post-partum. Results: Fifteen studies reported data on VTEs in pregnant women with an active malignancy. Underlying malignancy’s varied in the different studies. Eight of the studies reported data in patients with myeloproliferative diseases, and seven on other or multiple malignancies. In some studies preventive measures of VTEs were reported and consisted mainly of anticoagulant therapies. The incidence of VTEs ranged between 0.2% to 15%, and was highest in patients with myeloproliferative diseases, gynaecological malignancies, and acute leukaemia. Summary/Conclusion: Pregnant cancer patients seem to have a severe increased risk of VTEs, especially in certain subgroups. Because of the rare occurrence of malignant disease during pregnancy, these women should be monitored in a tertiary hospitals. Additionally thrombosis prophylaxis with low molecular weight heparin should be considered ante-partum and at least 6 weeks post-partum.
Abstract LB218: A safe and highly potent anti-PD-1-IL-2c fusion that decouples efficacy and toxicity of IL-2 therapy
Authors: Fan Ye, Jianing Huang, Zoey Huang, Sandra Chen, Eric Liao, Ella Li, Allison Quach, Jenny Jiang, Hanna Lin, Michael Hua, Savannah Yung, Lili Cheng, Ziyang Zhong
Journal: Cancer Research (2022)

Abstract Interleukin 2 (IL-2) is a pivotal immune agonist for tumor immunotherapy that has produced impressive clinical efficacy in a number of cancer types. Nevertheless, its pleiotropic effect has led to prohibitory side effects and immune restraint. In contrast, the PD-1 blockade-based cancer immunotherapy has a good safety profile by targeting and sustaining the activity of tumor-antigen specific T cells within cancer tissues. To take full advantage of complementary antitumor activity of PD-1 monoclonal antibody (mAb) and IL-2 as well as supreme intratumoral T-cell-targeting property of PD-1, a bifunctional fusion protein composed of PD-1 mAb and IL-2 mutein (αPD-1-IL-2c) is designed. IL-2c is a chimeric molecule that contains a fragment from IL-15 and does not bind to IL-2 receptor alpha (IL-2Rα). αPD-1-IL-2c stimulated greater pSTAT5 activation and proliferation in PD-1+ T cells than PD-1- T cells. αPD-1-IL-2c also induced a much stronger anti-tumor immune response compared to PD-1 mAb, IL-2c, or PD-1 mAb in combination with IL-2c in multiple syngeneic models such as B16F10, CT26, and MC38. In CT26 and MC38 models, αPD-1-IL-2c achieved complete response starting from 0.3 mg/kg dosing. In B16F10 model, αPD-1-IL-2c showed greater than 70% tumor growth inhibition (TGI). Global gene expression profiling studies showed that PD-1-IL-2c treatment significantly elevated expression levels of Cd3d, Cd3e, Cd8a, Il2rα, Cxcr3, Cxcr6, Zap70, Lck, and Pdcd1 in tumor tissues compared to treatment with PD-1 mAbs or IL-2c, indicating a specific expansion and activation of T cell in the tumor microenvironment (TME). The safety profile of αPD-1-IL-2c was assessed and compared to WT IL-2 and a leading “No-α” αPD-1-IL-2 fusion protein (αPD-1-IL-2x). WT IL-2 and αPD-1-IL-2x induced significant body weight loss and severe splenomegaly when dosed at 1.25 mg/kg. In contrast, αPD-1-IL-2c dosed at 10 mg/kg did not cause appreciable body weight loss and only led to minimal splenomegaly. In summary, we have developed a safe and highly potent αPD-1-IL-2 mutein that achieves full PD-1 blockade and TME-specific T cell activation and expansion without appreciable toxicity. Citation Format: Fan Ye, Jianing Huang, Zoey Huang, Sandra Chen, Eric Liao, Ella Li, Allison Quach, Jenny Jiang, Hanna Lin, Michael Hua, Savannah Yung, Lili Cheng, Ziyang Zhong. A safe and highly potent anti-PD-1-IL-2c fusion that decouples efficacy and toxicity of IL-2 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB218.
P924: TREATMENT EFFICACY OF PROGRESSION FREE SURVIVAL FOR REFRACTORY/RELAPSED MULTIPLE MYELOMA IN GERIATRIC PATIENTS: A NETWORK META-ANALYSIS
Authors: C.-H. Lee, C.-L. Ho
Journal: HemaSphere (2022)

Background: In recent 10 years, there were many studies explored the treatment efficacy of refractory/relapse multiple myeloma (R/R MM). Emerging evidences proved combination of new treatment modalities is significant better than traditional therapy. However, very few studies focus on geriatric patient who are more fragile and may not be able to tolerate treatment. Aims: Our aim was to synthesize all efficacy evidence, enabling an integrated comparison of all current treatment options in geriatric patients with R/R MM. Methods: We performed a systematic literature review to identify all publicly available randomized controlled trials (RCT) evidence. We searched Embase, PubMed, Cochrane Central Register of Controlled Clinical Trials, and the Web site www.ClinicalTrials.gov. Geriatric Patients with a diagnosis of R/R MM (including patients in second-line or more than second-line treatments) received subsequent active treatment were included. Geriatric patients should be set at least age 65 or above as a cut-off level. Data was extracted from subgroup analysis of each study. The evidence was synthesized using a Bayesian network meta-analysis. Hazard ratio (HR) was adopted. Results: In total, 4,966 citations were retrieved from the databases; 60 full texts were screened, of which 47 were excluded. In total, 13 RCTs were identified for quantitive analysis, including 14 treatment options (figure). Total 4337 geriatric patient were enrolled for network meta-analysis, twelve trials set cut-off level of age about 65, one set age 75 as a cut-off level. All trials had good quality. The triple combination therapy of daratumumab, lenalidomide and dexamethasone (DaraLenDex) was identified as the best treatment option in patients with R/R MM (figure). It was most favorable in terms of (1) HR for progression free survival (0.15; 95% credible interval (CI): 0.09 to 0.25) with significance and (2) probability of being best (96% of the cumulative ranking). Image:Summary/Conclusion: To the best of our knowledge, this is the first NMA on R/R MM that includes all regimens currently evaluated in randomized trials in elderly R/R MM. Our findings suggest that a 3-drug regimen containing the lenalidomide-dexamethasone backbone, preferentially combined with anti-MM mAbs daratumumab or elotuzumab, has the highest probability of being ranked as the best treatment in this setting, underlying the role of immunotherapy in MM. Prospective randomized trials are eagerly awaited to clarify the optimal sequencing of treatments for MM. We emphasize that it remains essential to conduct phase III RCTs to obtain more direct head-to-head evidence. Until such evidence becomes available, our results are highly important for informed decision making in everyday clinical practice
P1387: MONITORING OF DONOR CHIMERISM ON RED BLOOD CELLS ANTIGENS AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: A. Yovdiy, M. Smolnikova, E. Butina, E. Poponina, N. Zorina
Journal: HemaSphere (2022)

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for diseases of the blood system. One of the indicators reflecting the functioning of donor hematopoietic tissue is posttransplant chimerism. Aims: To evaluate the effect of ABO belonging of the donor and recipient on the timing of the formation of red blood cells (RBS) donor chimerism after HSCT. Methods: The study included 57 patients who underwent HSCT in 2013-2021. Patient age ranged from 3 to 60 years (median - 34). Diagnosis of the patients: acute leukemia - 42 persons, Hodgkin’s lymphoma - 6, aplastic anemia - 4 and other blood diseases - 5. Before HSCT, the study of RBC antigens of the ABO, Rh, Kell systems in donors and recipients was performed by gel agglutination using reagents and equipment BioRad (USA). Antigens identified in the recipient’s phenotype and absent in the donor’s phenotype were considered informative, or vice versa. For statistical data processing, the nonparametric Kruskal-Wallis test was used. Results: Thirty-two (56.1%) of 57 pairs differed in ABO system antigens. Of these, 16 pairs (28.1%) had a major ABO incompatibility, 16 pairs (28.1%) had a minor incompatibility. The time of appearance of donor’s RBS in patients with ABO incompatibility had a wider range (from 14 to 201 days) and occurred significantly later (Me - 28 days) than in recipients ABO identical with donors (Me - 20 days), and from minor ABO incompatibility (Me - 19 days) (Table 1). The periods of occurrence of 50% and 100% donor chimerism did not differ significantly in all groups. In the group of recipients with major ABO incompatibility a case of pure red cell aplasia was revealed. The first appearance of RBC carrying donor antigens was recorded on day 201. 100% donor chimerism was formed on day 278. Antibodies of the ABO system (anti-A) IgG were present in the recipient’s blood for 189 days, IgM - for 230 days. Table 1. - The emergence of chimerism depending on ABO compatibility of donor-recipient pairs ABO identical Minor ABO incompatibility Major ABO incompatibility р (n=25) (n=16) (n=16) First appearance of donor chimerism 20 (12-54) 19 (11-41) 28 (14-201) р<0.05 Ме (Min-Max days) 50% donor chimerism 41 (19-142) 41 (26-74) 54 (34-227) p>0.05 Ме (Min-Max days) 100% donor chimerism 138 (40-316) 110 (70-150) 141 (90-278) p>0.05 Ме (Min-Max days) Summary/Conclusion: In recipients with a major ABO incompatibility the first appearance of donor’s RBS after HSCT occurs significantly later than in couples ABO identical and couples with a minor ABO incompatibility.
“For Your Own Good”? Is It Ethical to Use Chemical Restraints on Patients Who Lack Capacity but Wish to Leave the Hospital against Medical Advice?
Authors: Leah R. Eisenberg
Journal: The American Journal of Bioethics (2022)

"“For Your Own Good”? Is It Ethical to Use Chemical Restraints on Patients Who Lack Capacity but Wish to Leave the Hospital against Medical Advice?." The American Journal of Bioethics, 22(7), pp. 93–94
Long‐term survival and life expectancy following an acute heart failure hospitalization in Australia and New Zealand
Authors: Saranya Hariharaputhiran, Yang Peng, Linh Ngo, Anna Ali, Sadia Hossain, Renuka Visvanathan, Robert Adams, Wandy Chan, Isuru Ranasinghe
Journal: European Journal of Heart Failure (2022)

Abstract Aims Contemporary long‐term survival following a heart failure (HF) hospitalization is uncertain. We evaluated survival up to 10 years after a HF hospitalization using national data from Australia and New Zealand, identified predictors of survival, and estimated the attributable loss in life expectancy. Methods and results Patients hospitalized with a primary diagnosis of HF from 2008–2017 were identified and all‐cause mortality assessed by linking with Death Registries. Flexible parametric survival models were used to estimate survival, predictors of survival and loss in life expectancy. A total of 283 048 patients with HF were included (mean age 78.2 ± 12.3 years, 50.8% male). Of these, 48.3% (48.1–48.5) were surviving by 3 years, 34.1% (33.9–34.3) by 5 years and 17.1% (16.8–17.4) by 10 years (median survival 2.8 years). Survival declined with age with 53.4% of patients aged 18–54 years and 6.2% aged ≥85 years alive by 10 years (adjusted hazard ratio [aHR] for mortality 4.84, 95% confidence interval [CI] 4.65–5.04 for ≥85 years vs. 18–54 years) and was worse in male patients (aHR 1.14, 95% CI 1.13–1.15). Prior HF (aHR 1.20, 95% CI 1.18–1.22), valvular and rheumatic heart disease (aHR 1.11, 95% CI 1.10–1.13) and vascular disease (aHR 1.07, 95% CI 1.04–1.09) were cardiovascular comorbidities most strongly associated with long‐term death. Non‐cardiovascular comorbidities and geriatric syndromes were common and associated with higher mortality. Compared with the general population, HF was associated with a loss of 7.3 years in life expectancy (or 56.6% of the expected life expectancy) and reached 20.5 years for those aged 18–54 years. Conclusion Less than one in five patients hospitalized for HF were surviving by 10 years with patients experiencing almost 60% loss in life expectancy compared with the general population, highlighting the considerable persisting societal burden of HF. Concerted multidisciplinary efforts are needed to improve post‐hospitalization outcomes of HF.
PB2124: MYC EXPRESSION ANALYSIS AND PROGNOSIS VALUE IN TRANSFORMED FOLLICULAR LYMPHOMA
Authors: J. Liang, K.-X. Du, W.-T. Wang, J.-Y. Li, W. Xu
Journal: HemaSphere (2022)

Background: Follicular lymphoma (FL) is the most common indolent lymphoma in the Western World, accounting for approximately 20-25% of all non-Hodgkin lymphomas. A subset of patients happened to high-grade transformation (HT) to the more aggressive diffuse large B cell lymphoma (DLBCL), associated with inferior clinical outcomes. MYC is an oncogene that occupies an important position in proliferation, apoptosis, and regulation of microRNA. Many human neoplasms show unscheduled MYC expression and it is important in pathogenesis of some lymphomas. Several RNA expression studies have identified MYC up-regulation as an important pathway in transformation of FL. Aims: This study aimed to investigate and quantify MYC expression in a series of FL with subsequent transformation. Furthermore, we tried to identify the role of MYC expression in transformed follicular lymphoma (tFL) and its prognosis value. Methods: We retrospectively analyzed a cohort of 414 patients newly diagnosed with FL treated at the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital) from June 2009 to April 2021. In addition, we performed RNA sequencing on 6 paired biopsies from 3 patients with FL with subsequent transformation to double-hit lymphoma (DHL). We combined our sequencing data with GSE142334. The dataset GSE142334 and GSE16131 were downloaded from Gene Expression Omnibus database (GEO). GSE142334 was gene expression profiling in paired tFL. GSE16131 were analyzed by survival data using the Kaplan–Meier method. Results: 414 FL patients were retrospectively analyzed in our study. Among them, 48 cases were stained for MYC in immunohistochemistry with 16 tFL. These 48 patients were divided into 4 groups, including MYC+ with transformation, MYC+ without transformation, MYC- with transformation and MYC- without transformation. The prevalence of MYC+ with transformation was 27.08%, found significant difference between MYC expression and transformation applied by chi-square test (Figure 1A, P=0.002). The 4 groups were analyzed by the Kaplan–Meier method for the survival curves, which MYC+ with transformation associated with worse PFS (Figure 1B, P=0.001). The MYC expression was significantly higher in tFL than in the corresponding FL (Figure 1C). It is worth noting that three cases showed lower MYC expression in the tFL sample, suggesting that MYC independent mechanisms are involved in transformation. From there, we took further analysis on survival data with GSE16131. MYC high expression contributed to adverse outcomes for OS (Figure 1D, P = 0.031). Image:Summary/Conclusion: MYC expression was uniformly high in tFL but much more heterogeneous and MYC high expression was associated with adverse outcomes in FL.